Myelinating glial function is fundamental for brain health and its impairment is detected in a growing number of psychiatric and neurological disorders. Studying the basic mechanisms regulating the progression of progenitors into myelinating oligodendrocytes in the developing and adult brain therefore has substantial implications for a better understanding of the mechanisms regulating proper brain function, while informing on potential causes for dysfunction, and providing the framework for the design of novel therapeutic strategies. Our lab has pioneered the concept of epigenetic regulation of oligodendrocyte progenitor differentiation. We identified DNA and histone changes responsible for repression of gene expression during developmental myelination and in adult remyelination, identified the responsible enzymes and defined their functional significance using transgenic mice, characterized them in the context of neuropathology and evaluated translational implications. We also reported impaired epigenetic regulation of oligodendrocyte differentiation in aging, in animal models of depression and in post-mortem Multiple Sclerosis human brains. We collaborated with chemical engineers to develop compounds with the ability to reverse some of the epigenetic changes. We also made unanticipated discoveries on the cross-talk between gut metabolites, social experiences, mechanical stimuli and myelination. In broad terms our objective is to understand the mechanisms that allow the chemical, metabolic and physical environment to induce a biological response in progenitor cells and result in the formation of myelin, proliferation and transformation of persistence of an undifferentiated state in the developing and adult brain. Our ultimate goal is to decipher the signals driving the differentiation of progenitors into myelinating glia, in order to inform on the design of regenerative strategies. In this application we propose an interdisciplinary approach, which includes the integration of several disciplines to develop new tools and experimental approaches for the discovery of novel modalities of signal transduction. We propose to use cell biology, biophysics, advanced imaging spectroscopy, nanotechnology and super resolution microscopy and new transgenic lines, epigenomic and proteomic approaches to addresses key open questions in the field. The proposed studies will develop new concepts and set the foundation on how progenitors interpret specific metabolic signals, mechanical forces, neuronal activity to regulate brain function. We expect that the results of the proposed experimental plan will set the stage for the development of novel therapeutic strategies for several neurological and psychiatric disorders, while advancing current knowledge of brain development and myelin formation.